Cefdinir intermediate

ABSTRACT

7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylic acid of formula I 
                         
in the form of a crystalline salt and use thereof, e.g. in the preparation of pure cefdinir.
 
     In another aspect this invention relates to the compound of formula I in the form of a salt, optionally in crystalline form, wherein the salt is selected from the group consisting of phosphate, hydrogen phosphate, mesylate, tosylate, sulfate, hydrogen sulfate and sulfamate.

The present invention relates to organic compounds, in particular thecompound(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (cefdinir). Cefdinir is an orally-administered cephalosporin withantibacterial properties, see e.g. The Merck Index Thirteenth Edition,Item 1933.

Production of cefdinir is not simple and cefdinir is not always obtainedin sufficient purity. For example, it is known that the preparation ofcefdinir of formula

may be carried out whereby the acyl side chain on the amino group inposition 7 of the cephalosporin ring structure may be introduced in theform of a (reactive) acid derivative of the 7-side chain, in which theoxime group is protected by an acetyl protecting group, after which theacetyl protecting group is cleaved in order to obtain cefdinir.

Published international application WO 98/45299 discloses a method forpurification of cefdinir by formation of a crystalline dicyclohexylaminesalt.

Now, surprisingly, intermediates e.g. crystalline intermediates havebeen found in the production of cefdinir, from which very pure cefdinirmay be obtained, so that production of highly pure cefdinir issimplified.

In one aspect, therefore, the present invention provides a compound offormula I

in the form of a crystalline salt.

It has surprisingly been found that the compound of formula I may beobtained in crystalline form in the form of a salt with a sulfonic orphosphonic acid or in the form of a salt with sulfuric acid, as hydrogensulfate or sulfate.

In a further aspect, the present invention provides the compound offormula I in the form of a crystalline salt with a sulfonic orphosphonic acid, or in the form of a crystalline salt with sulfuricacid, as hydrogen sulfate or sulfate.

In another aspect this invention relates to the compound of formula I inthe form of a salt, optionally in crystalline form, wherein the salt isselected from the group consisting of phosphate, hydrogen phosphate,mesylate, tosylate, sulfate, hydrogen sulfate and sulfamate. The newsalts of this invention may be in pure or substantially pure form, forexample displaying a purity of at least 90% by weight or more, e.g. 95%or greater, e.g. 98%, 99% or higher as determined by % HPLC area.

BRIEF DESCRIPTION OF THE DRAWINGS

Pages 1/14 and 2/14 of the Drawings is a list of equipment, samples,standards, and software, used to collect data.

Page 3/14 of the Drawings is Table 1 listing X-ray powder diffractometerdata for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid phosphate.

Page 4/14 of the Drawings is FIG. 1 is an X-ray powder diffractometergraph for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid phosphate.

Page 5/14 of the Drawings is Table 2 listing X-ray powder diffractometerdata for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrochloride.

Page 6/14 of the Drawings is FIG. 2 is an X-ray powder diffractometergraph for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrochloride.

Page 7/14 of the Drawings is Table 3 listing X-ray powder diffractometerdata for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid tosylate.

Page 8/14 of the Drawings is FIG. 3 is an X-ray powder diffractometergraph for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid tosylate.

Page 9/14 of the Drawings is Table 4 listing X-ray powder diffractometerdata for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrogensulfate.

Page 10/14 of the Drawings is FIG. 4 is an X-ray powder diffractometergraph for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrogensulfate.

Page 11/14 of the Drawings is Table 5 listing X-ray powderdiffractometer data for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid mesylate.

Page 12/14 of the Drawings is FIG. 5 is an X-ray powder diffractometergraph for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid mesylate.

Page 13/14 of the Drawings is Table 6 listing X-ray powderdiffractometer data for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid sulfate.

Page 14/14 of the Drawings is FIG. 6 is an X-ray powder diffractometergraph for7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid sulfate.

In the crystalline salts of the compound of formula I, the acid ispreferably a sulfonic or phosphonic acid of formula IIR₁YO₃H   IIin which R₁ signifies alkyl or optionally substituted aryl. Alkyl ispreferably (C₁₋₁₂)-alkyl, e.g. C₁₋₆alkyl, for example methyl, ethyl oroptionally branched (C₃₋₁₂)-alkyl. Aryl is preferably, for example,phenyl, methylphenyl (toluol) or naphthyl. Alkyl and aryl includesunsubstituted and substituted aryl and alkyl, for example arylsubstituted once or multiply by alkyl, for example (C₁₋₆)alkyl, such asmethyl, alkyloxy, e.g. (C₁₋₆)-alkoxy, or nitro;

Y denotes S or P.

Examples of crystalline salts according to the invention include saltsof the compound of formula I with an acid of formula HX, wherein X is agroup Cl⁻, HSO₄ ⁻, ½ SO₄ ²⁻, H₂NSO₃ ⁻, H₂PO₄ ⁻ and R₁YO₃ ⁻, wherein R₁and Y have the above-mentioned significances. Especially preferred saltsinclude the hydrogen chloride, phosphate, sulfate, methane sulfonate,benzene sulfonate and toluene sulfonate of the compound of formula I.

Most preferred salts are phosphate, toluene sulfonate and benzenesulfonate.

The salts and crystalline salts of this invention are useful asintermediates, for example in the production of cefdinir.

Acetyl-cefdinir of formula I in salt form, e.g. as crystalline salt withsulfonic or phosphonic acid, sulfuric acid, sulfamic acid, phosphoricacid or hydrochloric acid according to the present invention is referredto herein as “cefdinir intermediate”.

Cefdinir intermediates may contain crystal water or organic solventsbound therein. Cefdinir intermediates may therefore be present as such,or in the form of solvates, e.g. with organic solvents, or with water,for example in hydrated or partly hydrated form.

In another aspect, the present invention provides the compound offormula I in the form of a crystalline salt with a sulfonic- orphosphonic, sulfuric-, sulfamic-, phosphoric- or hydrochloric acid andin the form of a solvate, e.g. with an organic solvent or with water.

Crystallisation of the compound of formula I in the form of the saltaccording to one aspect of this invention, which is surprisinglysuccessful, represents a purification step of high efficiency inproduction processes for the production of cefdinir. By preparing thecefdinir intermediate, cefdinir can be obtained in outstanding purity,e.g. >95% purity, e.g. 98% by weight, 99% by weight or higher, e.g.99.5% by weight or higher, measured by % HPLC area. The content ofimpurities is very low, e.g. <5% by weight or less, e.g. 3% by weight,2% by weight, 1% by weight or less, e.g. 0.5% by weight, or even less.Further, purification of cefdinir may be effected at an earlier stage ofthe cefdinir production process than only at the final cefdinir stageitself.

Cefdinir intermediates may be produced e.g. as follows

-   -   Crystallisation by treating the compound of formula I in a        solvent with H₂SO₄, H₂NSO₃H, HCl, H₃PO₄ or an acid of formula        II,    -   Crystallisation by preparing the compound of formula I in        silylated form and treating it in a solvent with H₂SO₄, H₂NSO₃H,        HCl, H₃PO₄ or an acid of formula II in the presence of H₂O, or        in a silylatable protic solvent, e.g. an alcohol.    -   Reaction of 7-amino-3-vinyl-3-cephem-4carboxylic acid with a        reactive derivative of        syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic        acid in a solvent which is inert towards the reaction conditions        in order to produce the compound of formula I, and        crystallisation by treating the reaction mixture in a solvent        with H₂SO₄, H₂NSO₃H, HCl, H₃PO₄ or an acid of formula II,        optionally in a one-pot process.

Solvents which may typically be used for crystallisation may includee.g. alcohols, such as (C₁₋₆)-alcohols, ketones, e.g. (C₃₋₆)-ketones andethers, for example tetrahydrofuran (THF), and mixtures of two or moreof the said solvents, whereby water may optionally be present. Othersolvents may be present, e.g. inert solvents which may be used in aprocess for the production of the compound of formula I, for examplechlorinated hydrocarbons, such as CH₂Cl₂, nitrites, such asacetonitrile, and carboxylic acid esters, such as aceticacid-(C₁₋₄)-alkyl esters.

To produce the cefdinir intermediate, the free base of the compound offormula I may be suspended in one of the said solvents or solventmixtures, and crystallised by adding an acid of formula HX optionally inthe presence of water.

The compound of formula I may be produced by known methods. Preparationmay be carried out whereby 7-amino-3-vinyl-3-cephem-4-carboxylic acid insilylated form or as a salt with an amine or amidine or guanidine, e.g.DBU, DBN, TMG, or a tertiary aliphatic amine, is reacted with a reactivederivative ofsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid, forexample syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid mercaptobenzothiazolyl ester, in a solvent which is inert towardsthe reaction conditions, e.g. as indicated above.

Production of the cefdinir intermediate may take place after isolatingthe compound of formula I in crystalline salt form from the reactionmixture, or in a one-pot process directly in the reaction mixture, byadding the acid of formula HX, in which X is defined as above,preferably in the presence of the solvent which may be used forcrystallisation, as described above.

An equimolar amount of the compound of formula I and of the acid offormula HX may be used, whereby a slight excess of the acid, e.g. 1.1 to1.5 molar equivalents of HX per equivalent of compound of formula I, maybe of advantage. Higher excesses, for example two to five equivalents ofacid, may also be used. If a trialkylammonium salt or an amidine orguanidine salt of 7-amino-3-vinyl-3-cephem-4-carboxylic acid isacylated, in order to obtain the cefdinir intermediate at least twomolar equivalents of the acid of formula HX should be used. The amountof acid of formula HX which is to be used for crystallisation of thecefdinir intermediate therefore depends on the reaction conditions usedfor the production thereof.

In another embodiment the cefdinir intermediate may be obtained byadding the acid of formula HX to a suspension of the compound of formulaI in a solvent, e.g. as described above.

In another embodiment, the cefdinir intermediate may be crystallisedfrom a silylated compound of formula I by adding the corresponding acidof formula HX, e.g. the compound of formula I may be silylated by knownmethods, for example with N,O-bis-trimethylsilyl acetamide,N,O-bistrimethylsilyl trifluoroacetamide,monotrimethylsilyl-trifluoroacetamide, monotrimethylsilyl acetamide,hexamethyldisilazane or bis-trimethylsilyl urea, and an acid of formulaHX is added under the conditions described above.

In general, special measures are not needed to desilylate the compoundof formula I. For desilylation, generally the addition of the acid offormula HX and the addition of water or a silylatable protic solvent,e.g. an alcohol, are sufficient.

Cefdinir intermediates according to the present invention are especiallysuitable for producing cefdinir, since cefdinir may be obtained in highpurity.

The production of cefdinir from cefdinir intermediates may be carriedout for example by cleaving the acetyl protecting group on the oxygen ofthe oxime in the compound of formula I, whereby instead of the startingmaterials conventionally used, the cefdinir intermediate according tothe present invention is used as starting material. The acetylprotecting group is unstable both in acids and in bases, so that thisprotecting group may be cleaved in an acidic or basic medium. In acidicmedium, H₂SO₄ or sulfonic acids may be used e.g. as the acid, wherebycleavage may take place e.g. in an alcoholic or aqueous-alcoholicsolvent medium.

Typically, cleavage of the acetyl protecting group may be carried out ata temperature of between −5° C. and 15° C., for example between 0 and10° C.

In a basic medium, NH₃, NaOH or KOH or an alkaline earth carbonate, e.g.K₂CO₃, Na₂CO₃ or NaHCO₃, may be used e.g. as the base, whereby cleavagemay take place e.g. in an aqueous or aqueous organic solvent. Basicmedium, for example with a pH value of 7.5–9.5, e.g. 7.5–8.5, ispreferred.

Cefdinir may be crystallised in pure form from the reaction mixture,depending on the method used, by adding a base for cleavage in theacidic medium, or by adding an acid for cleavage in the basic medium.

In another aspect, the present invention provides a process for theproduction of cefdinir, which is characterised in that

-   a) the compound of formula I is prepared in the form of the    crystalline salt, optionally in form of a suspension, with a    sulfonic- or phosphonic-, sulfuric-, sulfamic-, phosphoric- or    hydrochloric acid,-   b) the crystalline salt of the compound of formula I is converted    into cefdinir by cleaving the acetyl group on the oxygen of the    oxime, and-   c) cefdinir is isolated, e.g. crystallised, from the reaction    mixture of step b).

In another aspect, the present invention provides the use of thecompound of formula I in the form of a crystalline salt for theproduction of cefdinir.

In a further aspect, the present invention provides a process for theproduction of cefdinir, which is characterised in that

-   a) a reactive derivative of the compound of formula III

syn2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid, e.g.syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyl-oxyimino)-acetic acidmercapto-benzothiazolyl ester, is reacted with a compound of formula IV

for example in reactive form, such as7-amino-3-vinyl-3-cephem-4-carboxylic acid in silylated form,

to obtain the compound of formula I

(6R,7R)7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid, in which the carboxylic acid is optionally silylated,

-   b) acid HX, in which X is as defined above and R₁ is as defined    above is added to the compound of formula I in order to obtain the    crystalline salt of the compound of formula I with acid HX,-   c) the crystalline salt from step b) is isolated,-   d) the crystalline salt of the compound of formula I from step c) is    converted into cefdinir by cleaving the acetyl group on the oxygen    of the oxime, and-   e) cefdinir is isolated from the reaction mixture of step d).

The reaction of the reactive derivative of the compound of formula IIIwith the compound of formula IV may be carried out under aproticconditions, e.g. in methylenechloride, acetonitrile or THF at atemperature of between 0 and 50° C., e.g. 20 to 40° C.

In a further aspect, the invention provides a process for the productionof syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercaptobenzothiazolylester, in which thesyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid isused as an ammonium salt, e.g. the tri-n-butylammonium salt, or an aminesalt e.g. triethylamine salt.

In a further aspect, this invention provides a process for theproduction of the active ester, e.g.syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercapto-benzothiazolylester, in which the compound of formula IIIis converted directly in water-moist form. “Water-moist” is understoodto mean e.g. up to 50% by weight, e.g. 20 to 40% by weight watercontent.

Thus both a special drying step and isolation of the dry product aredispensed with, thereby making the process simpler and more economicallyattractive.

The above processes are simpler and more economically attractive thanhitherto known processes.

In a further aspect, this invention provides a bulk quantity of cefdiniror cefdinir intermediate, for example 100 to 10,000 kg or more, e.g.15,000 to 50,000 kg in high purity, which is produced by any of theabove-described processes.

The following examples are intended to illustrate the invention morefully. Temperatures are indicated in ° C. and are uncorrected. Thefollowing abbreviations are used in the examples:

BSA bis(trimethylsilyl)acetamide BSU bis(trimethylsilyl)urea DMAcN,N-dimethylacetamide EtOH ethanol m.p. melting point HMDShexamethyldisilazane MeOH methanol MsOH methanesulphonic acid RT roomtemperature TEA triethylamine TMSI trimethylsilyl-iodide TsOHp-toluenesulphonic acidX-ray diffraction measurements of salts of7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid are summarised,respectively, in Tables 1 to 6 below and illustrated in FIGS. 1 to 6.

EXAMPLE 1(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(hydroxyimino)acetyl]amino]ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A solution of 6.0 g of7-[2-(2-aminothiazolyl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid in the form of a salt with TSOH in 20 ml of MeOH is mixed at 0°with 1.05 ml of concentrated H₂SO₄, the mixture obtained is stirred at≦10° and added dropwise to ca. 150 ml of an aqueous 3% NaHCO₃ solution.The pH value of the mixture obtained is adjusted to pH 5.0, 0.6 g ofactivated carbon are added, the mixture is stirred, and the activatedcarbon is filtered off and washed with H₂O. The filtrate obtained isheated to 25° to 30° and the pH value is adjusted to pH 3 with 2n H₂SO₄.(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid crystallises, is filtered off, washed and dried. Weighed product:3.09 g.

EXAMPLE 2 syn-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercapto-benzothiazolylester

10.0 g driedsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid(water content <1.0% by weight) are suspended at room temperature in 100ml of methylene chloride and then cooled to 0° C. 11.3 ml oftributylamine are added dropwise over the course of 10 minutes, andstirring is then effected for 15 minutes. The solution is mixed with18.6 g of bis-(benzothiazol-2-yl)-disulphide and stirred thoroughly for5 minutes. In a period of 20 minutes, 9.7 ml of triethylphosphite aredispensed in and the solution is stirred vigorously for 1½ hours at 0°C., subsequently cooled to −20° C. and stirred for a further 1½ hours.The yellowish crystalline product is filtered, washed three times, eachtime with 20 ml cold methylene chloride, and dried over night in avacuum at 30° C.

Weighed product: 15.6 g ¹H-nmr(DMSO-d₆) δ 2.22(s, 3H), 7.36(s, 1H),7.48(br s, 2H), 7.59(m, 2H), 8.09(m, 1H), 8.22(m, 1H)

EXAMPLE 3 syn-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercapto-benzothiazolylester

20.0 g syn-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)-acetic acid aresuspended in 100 ml of water and dissolved by adding 23 ml of 5M sodiumhydroxide solution. At a temperature of 20–28° C., 25.3 ml of aceticacid anhydride are slowly added dropwise, whereby the pH value of thesolution is held at between 7.0 and 7.5 by simultaneously adding 5Msodium hydroxide solution. Afterwards, stirring is effected for 60minutes at 25° C.

The solution is cooled to <10° C., and acidified to pH 3.0 over thecourse of 1 hour with 45 ml of conc. hydrochloric acid, wherebysyn-2-(2-aminothiazol4-yl)-2-(methylcarbonyloxyimino)-acetic acidcrystallises. The mixture is stirred for 60 minutes at <5° C., filteredand washed 3×, each time with 30 ml of cold water.

The water-moistened product thus obtained is suspended in 250 ml ofmethylene chloride and heated under reflux using a water separator untilthe water content of the suspension is ≦0.05% by weight.

28.3 ml tributylamine are added at 0° C. and stirring is effected for 15minutes. The solution is mixed with 46.5 g ofbis-(benzothiazol-2-yl)-disulphide and stirred thoroughly for 5 minutes.After the addition of 24.3 ml of triethylphosphite, stirring is effectedfor 90 minutes, and then cooling is effected to −20° C. The mixture isstirred at this temperature for 90 minutes, then filtered and washed 3×,each time with 50 ml of cold methylene chloride. The material is driedover night at 30° C.

Weighed product: 30.0 g ¹H-nmr(DMSO-d₆) δ 2.22(s, 3H), 7.36(s, 1H),7.48(br s, 2H), 7.59(m, 2H), 8.08(m, 1H), 8.22(m, 1H)

EXAMPLE 47-[2-(2-Aminothiazol-4-yl)-2(methylcarbonyloxylimino)acetamido]-3-vinyl-cephem-4-carboxylicacid.hydrochloride

120.0 g 3-vinyl-cephem-4-carboxylic acid are suspended in 1000 mldichloromethane and mixed with 167.1 ml BSA at RT. The mixture isstirred for 2 h and the clear solution obtained is cooled to 0° C. 147.6g syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetylchloride.hydrochloride are added over a period of/within 1 h andthe mixture stirred for 1 h at 0° C. The mixture is cooled to −10° C.and 69,9 ml TEA are added dropwise. The cold reaction solution is addeddropwise at RT over 1 h to a mixture of 75 ml water and 300 ml MeOH. Asuspension is formed which is stirred for 1 h at 0° C. Crystallineproduct is filtered off and washed twice, each time with 150 ml coldmethylene chloride. Isolated crystals are dried overnight at 35° C.under vacuum.

Yield: 225.2 g ¹H-nmr(DMSO-d₆) δ 2.21 (s,3H), 3.61&3.88(ABq, 2H,J=17.6Hz), 5.24(d,1H,J=4.8 Hz), 5.32(d,1H,J=11.4 Hz), 5.60(d,1H,J=17.5 Hz),5.83(dd,1H,J=4.8&7.9 Hz), 6.91 (dd,₁H,J=11.3&17.6 Hz), 7.21 (s, 1H),10.04(d, 1H,J=7.9 Hz) HCl: 6.7% m.p.: 140° C. (decomposition)

EXAMPLE 57-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid.methanesulfonate

5.0 g 3-vinyl-cephem-4-carboxylic acid are suspended in 50 mldichloromethane and mixed with 5.87 g BSU at RT. 20 μl TMSI are addedand the suspension is stirred for 2 h. The suspension is filtered andthe filter cake washed with 10 ml methylenechloride. The combinedfiltrates are mixed with 10 ml DMAc and 9,2 gsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino) aceticacid-mercaptobenzthiazolylester are added in 1 portion at 30° C.Stirring is continued for 2 h at 30° C. The mixture is cooled down to 0°C. and added dropwise to a solution of 1.9 ml MsOH in 10.5 ml EtOH and2.4 ml water. A thick suspension is formed which Is diluted with 100 mlmethylenechloride followed by stirring for 30 min at RT and for 1 h at0° C. Crystalline product is filtered off, washed three times, each timewith 25 ml cold methylenechloride, and dried at RT under vacuum.

Yield: 11.32 g ¹H-nmr(DMSO-d₆) δ 2.21 (s,3H), 2.41 (s,3H),3.61&3.88(ABq, 2H,J=17.7 Hz), 5.24(d,1H,J=4.9 Hz), 5.32(d,1H,J=11.4 Hz),5.61 (d,1H,J=17.5 Hz), 5.83(dd,1H,J=4.8&7.9 Hz), 6.91 (dd,1H,J=11.2&17.5Hz), 7.21 (s,1H), 10.02(d,1H,J=7.9 Hz) CH₃SO₃H: 16.4% m.p.: 170° C.(decomposition)

EXAMPLE 67-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid.para-toluenesulfonate

15.0 g 3-vinyl-cephem-4-carboxylic acid are suspended in 150 mldichloromethane and the mixture heated to boiling. 13.6 ml HMDS and 10μl TMSI are added and the mixture heated for 2 h under reflux conditionsand passing a nitrogen stream through the solution. The clear solutionis cooled to 30° C. and mixed with 30 ml DMAc. 27.6 gsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino) aceticacid-mercaptobenzthiazolylester is added in 1 portion and stirred for 3h at 30° C. The reaction mixture is added dropwise to a solution of16.40 g TsOH.hydrate in a mixture of 31.5 ml EtOH and 7.2 ml water. Theproduct crystallizes out. The suspension is diluted with 360 mlmethylene chloride and stirred for 60 min at 0° C. The crystallineproduct is filtered off and washed three times, each time with 75 mlcold methylene chloride, and dried under vacuum at 30° C.

Yield: 39.32 g ¹H-nmr(DMSO-d₆) δ 2.21 (s,3H), 2.28(s,3H), 3.61&3.89(ABq,2H,J=17.7 Hz), 5.25(d,1H,J=4.8 Hz), 5.32(d,1H,J=11.4 Hz), 5.61(d,1H,J=17.5 Hz), 5.84(dd,1H,J=4.8&7.9 Hz), 6.92(dd,1H,J=11.1&17.4 Hz),7.12&7.48(AA′BB′m,4H), 7.22(s,1H), 10.04(d,1H,J=7.9 Hz) Toluenesulfonicacid: 26.0% m.p.: 145° C. (decomposition).

EXAMPLE 77-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid.hydrogensulfate

5.0 g 3-vinyl-cephem-4-carboxylic acid are suspended in 50 mldichloromethane, mixed with 7.1 ml BSA at RT and stirred for 2 h. Themixture is warmed to 30° C. and 10 ml DMAc and 9.2 gsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercaptobenzthiazolylester added. Stirring is continued for 2.7 hat 30° C., the mixture cooled to 0° C., and a solution of 0.79 mlconcentrated sulfuric acid in a mixture of 10.5 ml EtOH and 2.4 ml wateradded dropwise. A suspension is formed which is diluted with 100 mlmethylenechloride, followed by stirring for 15 min at RT and 1 h at 0°C. The crystalline product is filtered off and washed twice, each timewith 25 ml cold methylenechloride and dried under vacuum at RT.

Yield: 10.58 g ¹H-nmr(DMSO-d₆) δ 2.20(s,3H), 3.61&3.89(ABq, 2H,J=17.7Hz), 5.24(d,1H,J=4.8 Hz), 5.32(d,1H,J=11.4 Hz), 5.60(d,1H,J=17.5 Hz),5.83(dd,1H,J=4.8&7.9 Hz), 6.91(dd,1H,J=11.2&17.5 Hz), 7.17(s, 1H),10.00(d, 1H,J=7.9 Hz) H₂SO₄: 10.7% m.p.: 150° C. decomposition

EXAMPLE 87-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carbonicacid.sulfate

21.43 g 3-vinyl-cephem-4-carboxylic acid are suspended in 214 mldichloromethane, mixed at RT with 15.68 ml HMDS and 29 μl TMSI, andheated under reflux for 2 h and passing a nitrogen stream through thesolution. The mixture is cooled to 30° C. and 42.9 ml DMAc and 39.4 gsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercaptobenzthiazolylester are added. Stirring is continued for 2.0h at 30° C., cooled to 0° C. and the reaction mixture added dropwise toa solution of 5.78 ml conc. sulfuric acid in 53.6 ml MeOH and 11.2 mlwater, on which a dense crystalline suspension is formed. Stirring iscontinued for 1 h at 0° C., the mixture filtered and the recoveredmaterial washed three times, each time with 107 ml cold methylenechloride, and dried under vacuum at RT.

Yield: 46.08 g ¹H-nmr(DMSO-d₆) δ 2.20(s,3H), 3.61&3.89(ABq, 2H,J=17.7Hz), 5.24(d,1H,J=4.8 Hz), 5.32(d,1H,J=1.4 Hz), 5.61 (d,1H,J=17.6 Hz),5.83(dd,1H,J=4.8&7.9 Hz), 6.91 (dd,1H,J=11.2&17.5 Hz), 7.18(s,1H),10.00(d,1H,J=7.9 Hz) H₂SO₄: 17.5% m.p.: 170° C. decomposition

EXAMPLE 97-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid.phosphate

21.43 g 3-vinyl-cephem-4-carboxylic acid are suspended in 214 mldichloromethane, mixed with 15.68 ml HMDS and 29 μl TMSI at RT andheated for 2 h under reflux conditions and passing a nitrogen streamthrough the solution. The mixture is cooled to 30° C. and 42.9 ml DMAcand 39.4 g syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-aceticacid-mercaptobenzthiazolylester are added. The mixture is stirred for2.0 h at 30° C., cooled to 0° C. and the reaction mixture added dropwiseat 0° C. to a solution of 7.0 ml 85% phosphoric acid in 53.6 ml MeOH and11.2 ml water, on which a thick crystalline suspension is formed. Thesuspension is diluted with 257 ml methylenechloride, stirred for 1 h at0° C. and filtered. The filter cake is washed once with a mixture of 90ml methylenechloride and 17 ml MeOH, and then twice more, each time with107 ml methylenechloride, followed by vacuum drying at RT.

Yield: 42.60 g ¹H-nmr(DMSO-d₆) δ 2.17(s,3H), 3.59&3.88(ABq, 2H,J=17.6Hz), 5.23(d,1H,J=4.8 Hz), 5.31(d,1H,J=11.4 Hz), 5.60(d, 1H,J=17.5 Hz),5.82(dd,1H,J=4.8&8.0 Hz), 6.90(dd,1H,J=11.2&17.6 Hz), 7.08(s,1H),9.91(d,1 H,J=8.0 Hz) H₃PO₄: 16.9% m.p.: 170° C. (decomposition)

X-ray Diffraction Measurements

X-ray diffraction measurements are made of the phosphate, hydrochloride,tosylate, hydrogensulfate, mesylate and sulfate salts of7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid. The results obtained anddiffraction patterns are shown respectively in the accompanying Tables 1to 6 and FIGS. 1 to 6.

1. The compound in the form of a crystalline salt which is7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido-3-vinyl-cephem-4-carboxylicacid phosphate having an X-ray powder diffraction pattern substantiallyas that shown in FIG.
 1. 2. The compound in the form of a crystallinesalt which is7-[2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid tosylate having an X-ray powder diffraction pattern substantiallyas that shown in FIG.
 3. 3. The compound in the form of a crystallinesalt which is7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid hydrogensulfate having an X-ray powder diffraction patternsubstantially as that shown in FIG.
 4. 4. The compound in the form of acrystalline salt which is7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid mesylate having an X-ray powder diffraction pattern substantiallyas that shown in FIG.
 5. 5. The compound in the form of a crystallinesalt which is7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3-vinyl-cephem-4-carboxylicacid sulfate having an X-ray powder diffraction pattern substantially asthat shown in FIG. 6.